MX2009002425A

MX2009002425A - Pharmaceutical composition comprising candesartan cilexetil.

Info

Publication number: MX2009002425A
Application number: MX2009002425A
Authority: MX
Inventors: Bertil Abrahamsson; Jonas Odman
Original assignee: Astrazeneca Ab
Priority date: 2006-09-05
Filing date: 2007-09-04
Publication date: 2009-03-20
Also published as: NO20090797L; KR20090049089A; AU2007293727A1; CA2662040A1; US20080058399A1; IL197093A0; CN101528224A; EP2063888A4; JP2010502698A; WO2008030161A1; BRPI0716445A2; EP2063888A1

Abstract

A pharmaceutical composition comprising as an active ingredient candesartan or candesartan cilexetil, the composition exhibiting a relative bioavailability, measured as area under the curve, of more than 1.5.

Description

PHARMACEUTICAL COMPOSITION THAT COMPRISES CANDESARTAN CILEXETILO Description of the Invention The present invention relates to a pharmaceutical composition comprising candesartan cilexetil, to a method for preparing such a composition, to a method for using such a composition in the manufacture of a medicament for use in therapy and to a method for treating a patient administering such a composition. Candesartan cilexetil is a prodrug of candesartan- a compound that inhibits the binding of candesartan cilexetil The bioavailability of a pharmaceutical active ingredient depends on several factors, a main factor is the solubility of the active in water. The speed limitation step for the absorption of a poorly soluble pharmaceutical active ingredient in water (ie one that requires more than 5000 g of water to dissolve 1 g in water) administered in solid form, is the dissolution of the active ingredient in water. The present invention provides a pharmaceutical composition comprising as an active ingredient candesartan cilexetil or candesartan, the composition exhibiting a relative bioavailability, measured as the area under the curve (AUC), of more than 1.5. According to one aspect of the invention, the active ingredient is in a substantially non-crystalline form. According to one aspect of the invention, the composition additionally comprises a solubilizer. According to one aspect of the invention, the relative bioavailability of the composition is more than 2. The pharmaceutical composition is solid at 25 ° C. The non-crystalline state of candesartan cilexityl can be obtained by dispersing the drug in a matrix comprising one or more solubilizers and or one or more water-soluble polymers, or by a process specifically designed for the precipitation of a pure drug in the desired state . According to one aspect of the invention, the pharmaceutical composition comprises the active ingredient and a solubilizer. According to one aspect of the invention, the composition comprises the active ingredient, a solubilizer, a disintegrant, a binder, and a lubricant. According to one aspect of the invention the composition comprises candesartan cilexetil, propylene oxide, starch, macrocrystalline cellulose I i na and sodium stearyl fumarate. A solubilizer is a compound that improves the solubility of another compound in water. Suitable solubilizers include: surfactants. The surfactants may be nonionic, ammonium, cationic or zwitterionic surfactants. Suitable nonionic surfactants include polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, polyoxyethylenealkyl ethers or sucrose esters. Suitable anionic surfactants include sodium dodecyl sulfate, sodium, 1,4-bis (2-ethylhexyl) sulfosuccinate or salts of fatty acids. Suitable cationic surfactants include alkyltrimethylammonium salts or dialkyldimethylammonium salts. Suitable zwitterionic surfactants include 3 - ((3-colamidopropyl) dimethylammonium) -1-propane or dodecyl-N-betaine sulfonate. Suitable nonionic surfactants with a hydrophilic predominance, having a hydrophilic-lipophilic balance of more than 12, include the polyoxyethylene esters of sorbitan or fatty acids (such as TWEEN 20 to 80), polyoxyethylene ether of a fatty alcohol (such as BRIJ). 56, 58, 78, 96, 98, 99 or Cremophor) or a block copolymer of ethylene oxide and propylene oxide (such as POLOXAM ER, for example PLURONIC F68 or F87). Water-soluble polymers can also be used to obtain candesartan cilexetil in a non-crystalline state. Water-soluble polymers include: alkylcellulose (such as methylcellulose), hydroxyalkylcellulose (such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropicellulose or hydroxybutylcellulose), hydroxyalkylalkylcellulose (such as hydroxyethylmethylcellulose or hydroxypropylmethylcellulose), carboxyalkylcellulose (such as carboxymethyl iron), an alkali metal salt of a carboxyalkylcellulose (such as sodium carboxymethylcellulose), carboxyalkylalkylcellulose (such as carboxymethylethylcellulose), carboxyalkylcellulose ester, starch, pectin (such as sodium carboxymethylamlopectin). ), a chitin derivative (such as chitosan), polysaccharide (such as alginic acid or an alkali metal or ammonium salt thereof, carrageenan, galactomannan, tragacanth, agar-agar, gum arabic, guar gum, xanthan gum or gelatin) ), polyacrylic acid or salt thereof (such as a polymethacrylic acid or a salt thereof, or a methacrylate copolymer), polyvinylalcohol, polyvidone (such as a copolymer of polyvidone with vinyl acetate and cross-linked polyvinylpyrrolidone) or a polyalkylene oxide (such as polyethylene oxide, polypropylene oxide or a copolymer of ethylene oxide and propylene oxide). In one aspect of the invention the water soluble polymer is polyvinylpyrrolidone or a copolymer of ethylene oxide and propylene oxide (a poloxamer). The ratio of candesartan cilexetil to the water soluble polymer can be from 1: 9 to about 9: 1, for example 1: 9 to 3: 1. A mixture of two or more water-soluble polymers can also be used in a composition according to the invention. Solid dosage forms include tablets (including, for example, immediate-release tablets, extended-release tablets, coated tablets, gel-coated tablets and enteric-coated tablets), capsules (e.g., soft gelatin capsules and hard gelatin capsules) ), granules or particles. Known excipients (eg bulking agents, binders, disintegrants, lubricants, glidants, surfactants) can be mixed with these systems specified above to provide the desired dosage form.The solid dispersions of the drug and carrier material can be prepared by a solvent method wherein the drug dissolves before being mixed with the carrier material and other excipients, Alternatively, the carrier material can be dissolved in the drug solution before being mixed with other excipients.

Alternatively, the solid dispersions can be prepared by grinding candesartan cilexetil together with the water-soluble carrier material. The solid dispersions can be prepared by the dissolution method followed by evaporation, melting followed by solidification or a combination of these methods. The fusion method requires that candesartan cilexetil and the water-soluble carrier be miscible in the fused state. When the solvent method is used, candesartan cilexetil and the water-soluble carrier dissolve in a mutual solvent which is removed (for example by evaporation under reduced pressure, spray-drying, freeze-drying, supercritical crystallization or other similar technique). The solid dispersions prepared by the solvent method are called coprecipitates or coevaporates. In the solvent-fusion method the dissolved candesartan cilexetil is added to the fused carrier. The solvent method comprises dissolving candesartan cilexetil in a volatile organic solvent containing at least one hydrophilic polymer carrier, and evaporating the solvent to dryness to form a coevaporation of candesartan cilexetil and the hydrophilic polymer carriers. The dissolution rate of the resulting coevaporate can be further increased by adding surfactant agents to the organic solvent before or after evaporation. Other additives may also be added such as a disintegrant. Suitable solvents include oxygenated solvents (such as an alcohol, ether or ketone, eg, ethanol, i-propanol, tetrahydrofuran, i-propyl ether, tetrahydropyran, acetone or methyl ethyl ketone) or chlorinated solvents (such as methylene chloride, chloroform or mixtures in various proportions of these same solvents). The fusion method comprises a) fusing at least one of the components and dispersing the other in this fusion or b) fusing all the compounds. At least one component can be a hydrophilic polymer. Other additives may also be added such as a surfactant or disintegrant. The small non-crystalline particles of candesartan cilexetil can be prepared by a spontaneous method of diffusion of emulsion solvent, which comprises the dissolution of candesartan cilexetil in a water-miscible organic solvent or a mixture of water-miscible organic solvents (such as methanol, ethanol, i-propanol, acetonitrile, acetone or dimethylphoroxide) followed by the precipitation of candesartan cilexetil by mixing the organic solvents with an aqueous phase. To prevent agglomeration, the aqueous phase preferably contains a hydrophilic polymer. The presence of an additive in the aqueous phase and / or in the Organic solvent can affect the rate of precipitation, resulting in different sizes of drug particles and different morphological states. Suitable additives include a polymer (for example polyethylene glycol, polyvinylpyrrolidone, methylcellulose or hydroxymethylcellulose), a salt (such as sodium chloride, calcium chloride or aluminum chloride), a viscosity-increasing agent (such as gelatin, acacia) or a co-solvent (such as glycerol or propylene glycol). The small particles can be collected by several methods, such as: centrifugation or ultracentrifugation, filtration, reverse osmosis followed by evaporation, evaporation of the solvent by heating and / or vacuum, dehydration by freezing, dehydration by aspersion, dehydration of the bed fluidized or a combination of any of the foregoing. The solid state of the small particles can be amorphous or partially crystalline when the precipitation is rapid, ie the rapid diffusion of the organic solvent in the aqueous phase (for example due to the similarities in the dielectric constants of the organic solvent and water ). If the diffusion process is slower, candesartan cilexetil can precipitate as crystals. The hydrophobic nature of candesartan cilexetil in relation to the aqueous solvent is also important for that class of particles is created, ie particle size and state morphologic. The following examples illustrate the invention. Examples In this section, the materials, preparation techniques and analytical methods used in the following examples are described. Where it is used, candesartan cilexetil (abbreviated with ce), CREMOPHOR RH40 ™ (a castor oil hydrogenated with polyoxyl 40), polyethylene glycol 6000, polyvinylpyrrolidone K90, corn starch, aluminum silicate, mannitol, AVICEL ™ (a microcrystalline cellulose), cross-linked polyvinylpyrrolidone, magnesium stearate, sodium stearyl fumarate (PRUV) and ethanol (95%) were supplied by Astra AB, Poloxamer 188 (PLURONIC F68 ™) was supplied by BASF and polysorbate 20 (TWEEN 20 ™) was supplied by Acros . The medium used for the solution was 500 ml of 0.2% polysorbate 20 in 0.05 M phosphate buffer pH 6.5 with a blade speed of 75 rpm (11 USP dissolution apparatus). In all dissolution tests, 8 mg of candesartan cilexetil was added to the medium (except where not indicated). After extraction with 60% (v / v) acetonitrile in water (filter of 0.45μ? T? Pore size), the amount of candesartan cilexetil was determined by liquid chromatography and UV detection at 254 nm. The particles were studied under a microscope electronic scanning (JEOL JSM-5400). Dispersions and particles were studied by FT-Raman (Perkin Elmer 2000). Example 1 This example illustrates the preparation of a solid dispersion of candesartan cilexetil in Poloxamer 188 and was prepared by a melt-solidification method. Part A Candesartan Cilexetil 10-20% Poloxamer 188 80-90% A mixture of candesartan cilexetil in the form of crystalline powder and Poloxamer 188 was heated to about 70 ° C for about 5 minutes (ie above the melting temperature of the polymer but below the fusion of the active compound) and the mixture was allowed to cool naturally. After solidification at room temperature the dispersion was ground using a Stomacher. The resulting particles were sieved through a 0.7 mm sieve. It was found that the active compound in the dispersion was crystalline by Raman analysis.

Fármaco Fármaco Fármaco Drug dissolved dissolved dissolved dissolved after after after after after 5 minutes 10 minutes 15 minutes 20 minutes ce 24 43 54 61 Physical mixture 28 44 55 61 of 20% ce. and Poloxamer 188 10% of ce. 57 74 81 86 in Poloxamer 188 20% ce 48 68 79 84 in Poloxamer 188 Part B: Formation of a tablet The crushed fusion of part A was mixed with an immediate release granulate (containing mainly microcrystalline cellulose and corn starch) in a ratio of 1: 2 to 1: 5 (part A to granulate) and the tablets were made by the compression of the resulting mixture. The tablet disintegrated in an aqueous solution in a period of 10 minutes at 37 ° C.

* The tablet contained 7.7 mg of ce. Example 2 This example illustrates the preparation of a solid dispersion of candesartan cilexetil in polyethylene glycol 6000 prepared by a melt-solidification method. Part A Candesartan Cilexetil 10-20% Polyethylene glycol 6000 (PEG 6000) 80-90% A physical mixture of candesartan cilexetil and PEG 6000 was heated to about 70 ° C (i.e., above the melting temperature of polymer, but well below the melting of the active compound) for about 5 minutes and the mixture was left cool naturally After solidification at room temperature the dispersion was ground using a Stomacher. The resulting particles were sieved through a 0.7 mm sieve. It was found that the drug in the dispersion was crystalline by Raman analysis.

Fármaco Fármaco Fármaco Drug dissolved dissolved dissolved dissolved after after after after after 5 minutes 10 minutes 15 minutes 20 minutes ce 24 43 54 61 10% ce. at 63 78 84 88 PEG 6000 20% ce in 41 58 68 78 PEG 6000 Physical mixture 28 45 55 63 of 20% ce and PEG 6000 Part B: Formation of a tablet In a method similar to that of part B of Example 1, the ground dispersion was mixed with an immediate release granulate and the tablets were made. The tablet disintegrates in an aqueous solution in a period of 10 minutes at 37 ° C.

Drug Drug Drug Drug dissolved dissolved dissolved dissolved after after after after 5 minutes 10 minutes 15 minutes 20 minutes Candesartan 24 43 54 61 cilexetil (ce) Tablet with 54 70 78 84 dispersed solid n of 10% ce. in PEG 6000 * Tablet with 53 71 79 85 dispersed solid 20% ce. in PEG 6000 ** * The tablet contained 7.5 mg of ce. ** The tablet contained 8.1 mg ce Example 3 This example illustrates the preparation of a tablet comprising a solid dispersion of candesartan cilexetil in polyvinylpyrrolidone K90 and was prepared by a dissolution-evaporation method. Candesartan Cilexetil 45% Polyvinylpyrrolidone K90 (PVP K90) 55% Candesartan cilexetil was dissolved (45 mg / ml), together with 7% (w / w) PVP K90, in ethanol. The resulting solution was used as a granulation liquid with a bed of microcrystalline cellulose powder, mannitol and aluminum silicate to form an immediate release granulate. After drying at 50 ° C the resulting mixture was compressed to form tablets. The tablets were disintegrated in an aqueous solution in a period of 10 minutes at 37 ° C. It was found that the drug in the dispersion was amorphous by Raman analysis.

Drug Drug Drug Drug dissolved dissolved dissolved dissolved after after after after 5 minutes 10 minutes 15 minutes 20 minutes ce 24 43 54 61 Drug Drug Drug Drug dissolved dissolved dissolved dissolved after after after after 5 minutes 10 minutes 15 minutes 20 minutes Tablet with 53 69 84 solid dispersion of 45% ce. in PVP K90 * The tab contained 7.8 mg. Example 4 This example illustrates the preparation of a solid dispersion of candesartan cilexetil in polyvinylpyrrolidone K90 and was prepared by a dissolution-evaporation method with the addition of a surfactant. Candesartan cilexetil 31% or 21% PVP K90 38% or 26% CREMOPHOR RH40 31% or 53% The active compound was dissolved (45 mg / ml), together with 7% (w / w) PVP K90 and CREMOPHOR RH40 (45 or 112.5 mg / ml) in ethanol. The tablets were formed using the methodology of Example 3. One tablet disintegrated in an aqueous solution in a period of 10 minutes at 37 ° C. It was found that the drug in the dispersion was partially crystalline by Raman analysis.

Fármaco Fármaco Fármaco Drug dissolved dissolved dissolved dissolved after after after after after 5 minutes 10 minutes 15 minutes 20 minutes ce 24 43 54 61 Tablet with 56 68-83 dispersed solid 45% ce. in PVP K90 and with Cremophor RH40 (1 mg / mg ce) * Tablet with solid dispersion of 45% ce. in PVP K90 and with Cremophor RH40 (2.5 mg / mg e) ** The ta fle contained 8.0 mg * The tablet contained 7.9 mg Example 5 This example illustrates the preparation of the non-crystalline candesartan cilexetil particles having a diameter of 250-350 nm. The active compound was dissolved (10 mg / ml) in 30 ml of ethanol. This solution was added slowly to the aqueous solution of 1.5% (w / w) PVP K90 (125 ml) and the particles were formed. The particle suspension was washed with water during the centrifugation and the volume of water was reduced to approximately 2-3 ml. The suspension was mixed with an equal volume of 10% (w / w) PVP in water and was used as a granulation liquid (5% PVP K90) with a premix of microcrystalline cellulose powder, mannitol and Primojel to form a granulate of immediate release that was compressed to form the tablets. One tablet disintegrated in an aqueous solution in a period of 10 minutes of contact with water at 37 ° C. It was found that the particles formed were completely amorphous by Raman analysis.

Drug Drug Drug Drug dissolved dissolved dissolved dissolved after after after after 5 minutes 10 minutes 15 minutes 20 minutes ce 24 43 54 61 Tablet with 75 90 96 98 small amorphous particles * * The tablet contained 5.4 mg of drug. Example 6 This example illustrates the preparation of candesartan cilexetil amorphous particles having a diameter of 1-3 μ. The active compound was dissolved (60 mg / ml) in 10% PVP K90 (w / w) in ethanol. This solution was slowly added to an equal volume of an aqueous solution of 1.5% (w / w) PVP K90 and the particles formed. The particle suspension was used as a granulation liquid (5.3% (w / w) PVP K90) with a premix of microcrystalline cellulose powder, mannitol and Primojel to form an immediate release granulate which was compressed to form the tablets. . A tablet disintegrated in an aqueous solution in a period of 1 O minutes at 37 ° C. It was found that the particles were mainly amorphous (certain crystalline content) found by the Raman analysis.

* The tablet contained 6.6 mg of drug. Although the particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications of the present invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all modifications that are within the scope of this invention. Example 7 The bioavailability for solid dispersions (Poloxamer 188) and for small amorphous particles was studied in rats. The dispersions were administered orally while the powders and particles were administered in suspensions. The relative bioavailability in the rat for candesartan cilexetil administered as a suspension is 19% and administered in a solution is 50%. The suspension with small amorphous drug particles had a relative bioavailability of 40%. The relative bioavailability for the solid dispersion of candesartan cilexetil in Poloxamer 188 was 25%. Example 8 Bioavailability was determined in human volunteers for a tablet (a) which contained candesartan cilexetil mainly in non-crystalline form, a tablet (b) which contained mainly the crystalline drug dispersed in a tablet matrix consisting of a hydrophilic polymer of rapid dissolution in relation to a standard tablet (c) that mainly includes the crystalline drug. All tablets contained 32 mg of candesartan cilexetil. The study was performed according to a cross-over design and each tablet was administered as a single dose to 15 healthy volunteers. The The relative bioavailability of tablets A and B in relation to tablet C was determined from the area under the curve (AUC) of the plasma concentration-time curves of candesartan. The average AUC ratio for tablet A in relation to tablet C was 2.55, that is, the bioavailability was more than doubled for tablet A compared to the standard tablet. The corresponding AUC ratio for tablet B was 1.24 and nothing statistically significant (p> 0.05) was detected for this tablet compared to the reference. Composition of tablet A Ingredients for 2000 tablets Candesartan Cilexetil 16 g Corn starch 107 g Microcrystalline cellulose 288 g Sodium stearyl fumarate 5 g Poloxamer 18 64 g Water, purified * es. * Used in the manufacturing process, but eliminated during dehydration. Composition of tablet B Ingredients for 2000 tablets Candesartan Cilexetil 16 g Aluminum silicate 20 g Ethanol 95% (v / v) * c.s. Magnesium stearate 4.6 g Mannitol 40 g Microcrystalline cellulose 256 g Polyoxyl 40 hydrogenated castor oil 40 g Polividone, crosslinked 64 g Polyvinylpyrrolidone, K90 20 g * Used in the manufacturing process but removed during dehydration. Composition of the tablet C The tablet C is an 8 mg tablet of candesartan cilexetil available commercially sold under the name of ATACAND ™ by AstraZeneca AB.

Claims

1. A pharmaceutical composition comprising candesartan cilexetil or candesartan as the active ingredient, the composition exhibits a relative bioavailability, measured as the area under the curve (AUC), of more than 1.5.

2. A pharmaceutical composition according to claim 1, wherein the active ingredient is in a substantially non-crystalline form.

3. A pharmaceutical composition according to claim 1 or 2, wherein the composition additionally comprises a solubilizer.

4. A pharmaceutical composition according to any of the preceding claims, wherein the relative bioavailability is more than 2.